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Rapamycin and Minocycline Treatment Does Not Rescue Behavioral and Molecular Changes Induced by Early-Life Seizures
Sydney F Pell1, Katherine J Blandin1, Taylor R Bradish1
1Department of Psychology and Neuroscience, Baylor University, Waco, TX 76798, USA.
Abstract:
Early-life seizures lead to long-term behavioral deficits, stimulate cytokine release, and disrupt the intracellular PI3K/AKT/mTOR signaling pathway. This study examined whether inhibiting the mTOR pathway, neuroinflammatory signaling, or both reduces behavioral comorbidities in adulthood. Female C57BL/6J mice received kainic acid on postnatal day 10 to induce status epilepticus. Three hours later, the mice were treated with saline, minocycline, rapamycin, or both. Three months later, behavioral assessments were conducted that measured activity, anxiety, social behavior, repetitive behavior, and learning. Early-life seizures resulted in social behavior deficits in the social chamber test, altered anxiety in the elevated plus maze, and an increase in repetitive behavior in the nose poke assay. Rapamycin and minocycline/rapamycin groups showed reduced distance traveled in the saline groups. We did not find any changes in cytokines IL6, IL-1β, and TNFα in the hippocampus or cortex using RT-qPCR. Through Western blotting, we found that rapamycin reduced the phosphorylated S6 levels. Minocycline decreased phosphorylated S6 in controls, but restored phosphorylated S6 levels in the seizure group. Early-life seizures had long-term impacts on behavioral comorbidities. Rapamycin and minocycline, alone or combined, did not restore the behavioral or molecular changes after early-life seizures. These findings clarify the behavioral outcomes after early-life seizures and therapeutic modulation.
Insights
Early-life seizures cause lasting behavioral issues. Inhibiting the mTOR pathway or neuroinflammation did not reverse these deficits in adult mice, indicating limited therapeutic potential.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Pharmacology
Background:
- Early-life seizures (ELS) can result in persistent behavioral deficits.
- These seizures disrupt intracellular signaling pathways like PI3K/AKT/mTOR and trigger neuroinflammation.
- Understanding therapeutic interventions for ELS-induced comorbidities is crucial.
Purpose of the Study:
- To investigate if inhibiting the mTOR pathway or neuroinflammatory signaling, alone or in combination, can mitigate long-term behavioral comorbidities following ELS.
- To assess the impact of rapamycin (mTOR inhibitor) and minocycline (anti-inflammatory) on behavioral and molecular changes in a mouse model of ELS.
Main Methods:
- Female C57BL/6J mice underwent kainic acid-induced status epilepticus on postnatal day 10.
- Post-seizure treatments included saline, minocycline, rapamycin, or a combination.
- Behavioral assessments (activity, anxiety, social interaction, repetitive behaviors, learning) and molecular analyses (cytokine levels, S6 phosphorylation) were performed three months later.
Main Results:
- ELS induced social deficits, altered anxiety, and increased repetitive behaviors in adulthood.
- Rapamycin and minocycline/rapamycin treatments did not restore these behavioral deficits.
- No significant changes in key inflammatory cytokines (IL-6, IL-1β, TNFα) were detected.
- Rapamycin reduced phosphorylated S6 levels; minocycline's effect on S6 phosphorylation varied between control and seizure groups.
Conclusions:
- Early-life seizures induce enduring behavioral comorbidities.
- Neither mTOR inhibition nor neuroinflammation suppression, alone or combined, effectively reversed these long-term behavioral or molecular alterations.
- These findings highlight the complexity of ELS sequelae and the limited efficacy of the tested therapeutic strategies.
